Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Reissue Patent
1999-11-10
2001-11-13
Coleman, Brenda (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
C540S479000, C546S051000
Reissue Patent
active
RE037449
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to the synthesis of dimer alkaloid compounds, particularly those of the Catharantus (Vinca) family, such as vinblastine, vincristine and leurosidine, sometimes referred to hereinafter as the target compounds or the target dimer alkaloid compounds.
The dimeric alkaloids of present interest have remarkable anti-viral, anti-tumor and anti-leukemic properties. In the past, these alkaloids were isolated from the Catharantus species, particularly C. roseus, in small quantities. More recently, progress has been made in the synthesis of these compounds (U.S. Pat. Nos. 4,144,237 and 4,279,817 to James P. Kutney, and parent application U.S. Ser. No. 07/011,810). Unfortunately, these prior art methods also yielded small quantities of the target compounds. The present invention overcomes the difficulties encountered in the prior art insofar as it yields dramatically increased quantities of the target dimer alkaloid compounds.
SUMMARY OF THE INVENTION
The present invention relates to the multi-step process for preparing dimer alkaloid compounds, particularly those of the Catharantus (Vinca) family, such as vinblastine, vincristine and leurosidine, as described in parent application U.S. Ser. No. 07/011,810, filed Feb. 6, 1987, the disclosure of which is incorporated herein by reference.
Briefly, the present process comprises the following steps:
(a) forming an N-oxide derivative in the cold at a temperature of from about −77° to about +40° C., from an indole unit having a bridge nitrogen, by oxidizing the bridge nitrogen and without isolating said derivative;
(b) treating said N-oxide derivative in the presence of at lest one member selected from the group consisting of acetic anhydride, halogenated acetic anhydride, and acetyl chloride, to effect a polonovski-type fragmentation reaction;
(c) without isolating the product of step (b), stereospecifically coupling said product of step (b) with a dihydroindole unit in the presence of at least one member selected from the group consisting of acetic anhydride, halogenated acetic anhydride, and acetyl chloride at a low temperature of about −70° C. to about +40° C., under inert conditions, to form a first iminium intermediate;
(d) reducing said first iminium intermediate by reaction with a 1,4-dihydropyridine compound, thereby forming an enamine;
(e) preparing a second iminium intermediate by oxidative transformation of the enamine obtained in step (d) under controlled aeration conditions; and
(f) reducing the product obtained in step (e) to form the target dimer alkaloid compounds.
All of the above steps can be conducted in a one-pot operation from the reaction of the indole unit and the dihydroindole unit to the final products without isolation of the intermediates.
REFERENCES:
patent: 4144237 (1979-03-01), Kutney
patent: 4199505 (1980-04-01), Szantay et al.
patent: 4279817 (1981-07-01), Kutney
patent: 4305875 (1981-12-01), Potier et al.
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patent: 4778885 (1988-10-01), Vukovic et al.
patent: 4841045 (1989-06-01), Kuehne
patent: 2558124 (1976-07-01), None
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patent: 3826412 (1989-02-01), None
Kutney et al., Helvetica Chimica Acta, 59(8), pp. 2858-2882, 1976.
Fieser et al., “Reagents for Organic Synthesis”, 6 pp. 36-37, Wiley-Interscience, John Wiley & Sons, New York, 1987.
Nishiyama et al., Chem. Abstr., 84: 179294h, 1976.
Nakumura et al., Chem. Abstr., 101: 229474j, 1984.
Langlois et al., Tetrahedron Letters, 14, pp. 1099-1102, 1976.
Mangeny et al., J. Am. Chem. Soc., 101(8), pp. 2243-2245, 1979.
Kutney et al., Heterocycles, 27(8), pp. 1845-1853, Aug. 1988.
Boulet Camille A.
Choi Lewis S. L.
Kutney James P.
McHugh Michael
Nakano Jun
Coleman Brenda
Jenkens & Gilchrist
University of British Columbia
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